The recent demonstrations of associations between human histocompatibility (HLA) antigens and a large number of diseases have opened up new approaches which help to clarify the genetics and aetiology of many of these diseases. Our preliminary studies in the development of models to determine the mode of inheritance of the HLA associated diseases have led to a better understanding of the inheritance pattern in ankylosing spondylitis, insulin dependnent juvenile diabetes, multiple sclerosis, hemochromatosis, celiac disease and dermatitis herpetitomis. It is now clear that the original simple models investigated are not always sufficient to explain the inheritance patterns of the HLA associated diseases. The primary focus of our proposed research program is to develop more refined and realistic models to study the inheritance patterns of the HLA associated diseases. We aim to investigate several models of disease redisposition. These include two locus disease models and single locus intermediate models, also models where the HLA antigen(s) themselves predispose to disease versus disease predisposition by a closely linked locus. We will also extend these models to allow for possible disease heterogeneity, and clustering of certain diseases. We will relate our findings to population and family data and devise statistical analyses to test the various models. We will continue and extend our interests in development of models relevant to the interpretation of population data. We anticipate that these studies will provide a strong theorectical basis upon which more reliable inferences can be made regarding the forces acting in natural populations.